Mechanistic Studies on Arsenic Toxicity in Endothelial Cells

Abstract

Arsenic is a well-established human toxin. Over 200 million people worldwide are exposed to arsenic, mainly through drinking water. Recently, several epidemiological studies have reported that even low concentrations of arsenic impair neurological functions across a broad age range in human [1]. However, the cellular and molecular mechanisms of arsenic’s effect on the central nervous system (CNS) are not well understood. The blood-brain barrier (BBB) is a complex multicellular structure separating the CNS from the systemic circulation and protects the neural tissue from toxins and pathogens. Alterations in the BBB are an important component of pathology in many neurological disorders [2]. Therefore, arsenic may have a toxic impact on the BBB and thus affect the function of CNS. Since brain endothelial cells (BECs) are the major component of the BBB and play important roles in maintaining the functional integrity of brain tissue under toxic exposure, we focused on arsenic-induced alterations in BECs in our study. Previously, our laboratory has reported that reactive oxygen species (ROS) play an important role in an arsenic-induced increase in brain endothelial cell permeability[3]. However, the underlying mechanism of arsenic-induced ROS generation in endothelial cells and how ROS regulate endothelial cell functions are unclear. Mitochondria are considered as the major source of ROS generation in mammalian cells and arsenic-induced mitochondrial dysfunction has been reported in many studies, which suggest that it may be associated with arsenic-induced oxidative stress in endothelial cells (ECs). In addition, autophagy, which is regulated by oxidative stress, plays an important role to control endothelial permeability and maintain redox balance in ECs and it may also be involved in arsenic toxicity in BECs [4].